Synthesis and Applications of Arginine Mimetics

Protein‐protein, protein‐RNA, and protein‐DNA interactions are broadly mediated through the guanidinium functionality of arginine residues. However, specific recognition by arginine is limited, because the guanidinium functionality is attached to a linear alkyl group. To achieve specific molecular recognition, arginine mimetics are used, which place functional groups adjacent to a guanidinium. In order to specifically target arginine‐mediated recognition, we developed convenient syntheses of alpha‐ guanidino acids, in which the amine of an amino acid is converted into a guanidinium. The alpha‐substituted guanidiniums of guanidino acids and the side chain of the amino acid work synergistically toward molecular recognition with greater affinity for the target site. We have designed arginine mimetics for specific and high affinity molecular recognition by coupling protected guanidino acids to alcohol and amine nucleophiles. Protected guanidino acids of Gly, Phe, Val, and Leu were readily synthesized from methyl esters of alpha‐amino acids by guanylation of the amine with bis‐boc‐thiourea and Mukaiyama’s reagent. guanidino acids, with a free carboxylic acid for coupling to nucleophiles, were generated by saponification of the methyl ester using LiOH. Arginine mimetics were synthesized by coupling protected guanidino acids to hydroxyl and amino groups to generate complex alpha‐substituted guanidiniums. Molecules containing alpha‐guanidino acids were applied to specific protein and RNA recognition. I would like to thank the National Institute of Health and Howard Hughes Medical Institute for funding for this project.